Low dose colonic cleansing system

ABSTRACT

A method of colonic cleansing that includes administering orally a first dose and a second dose of a liquid osmotic colonic evacuant composition. The second dose includes an amount of the liquid osmotic colonic evacuant composition that is 55% to 95% of the amount of the first dose.

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/822,703 entitled “Flavored Colonic Cleansing System” filed Aug. 17,2006, which is incorporated by reference in its entirety.

BACKGROUND

Aqueous solutions of sodium phosphate salts (monobasic and dibasicsodium phosphate), such as FLEET® PHOSPHO-SODA®, are very effective oralcathartics and are extensively used prior to colonoscopy, radiographicprocedures, and surgery. For pre-colonoscopy use, a split regimen ispreferred that includes one 45 mL dose given the evening beforecolonoscopy and a second 45 mL dose given at least three hours prior tothe procedure on the following morning. Each 45 mL dose contains 21.6 gmonobasic sodium phosphate, and 8.1 g dibasic sodium phosphate. Patientsare instructed to consume only a clear liquids diet for the mealproceeding the first dose, and to drink large amounts of clear liquids,including water and oral rehydration solutions, for example 3 to 4liters, after each dose. See, for example, US Published PatentApplication publication no. US20040192614 to Vanner et al.

SUMMARY

In a first aspect, the invention is a method of colonic cleansing,comprising administering orally a first dose of a liquid osmotic colonicevacuant composition; and administering orally a second dose of theliquid osmotic colonic evacuant composition. The second dose comprisesan amount of the liquid osmotic colonic evacuant composition that is 55%to 95% of the amount of the first dose of the liquid osmotic colonicevacuant composition.

In a second aspect, the invention is a kit for colonic cleansing,comprising a first dose of an osmotic colonic evacuant composition; anda second dose of the osmotic colonic evacuant composition. The seconddose comprises an amount of the osmotic colonic evacuant compositionthat is 55% to 95% of the amount of the first dose of the osmoticcolonic evacuant composition. The osmotic colonic evacuant is not in theform of tablets or capsules.

In a third aspect, the invention is a kit for colonic cleansing,comprising an osmotic colonic evacuant composition; and at least onedosage container. The at least one dosage container has markings todenote a first dose and a second dose, and the second dose comprises anamount that is 55% to 95% of the amount of the first dose.

In a fourth aspect, the invention is a method of colonic cleansing witha low dose colonic cleansing system, comprising administering orally 45mL of an osmotic colonic evacuant composition; and administering orally30 mL of the osmotic colonic evacuant composition. The low dose coloniccleansing system comprises 0.45 gram/mL of monobasic sodium phosphateand 0.18 gram/mL of dibasic sodium phosphate when solubilized in water,at least one packet comprising a flavorant, and at least one dosagecontainer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts components of the kit for one preferred embodiment of thelow-dose colonic cleansing system.

DETAILED DESCRIPTION

Because a hypertonic solution of sodium phosphate salts acts as anosmotic colonic evacuant of limited duration, it was previously thoughtthat the administration of two equivalent doses of the salt catharticsolution was necessary to promote effective colonic cleansing. Thepresent invention is drawn to the unexpected and surprising finding ofeffective phosphate salt-based colonic cleansing systems that employ asecond dosage amount smaller than required previously.

The present invention makes use of the discovery of effective coloniccleansing systems when administered in dosages lower than that requiredin the past. In particular, the present invention makes use of theunexpected and surprising finding that colonic cleansing can beaccomplished that is sufficient for colonoscopy by using a smaller dosecolonic cleansing system that includes two doses of an osmotic colonicevacuant, where the second dose is reduced. Thus, the inventiondescribed herein achieves effective colonic cleansing using a smallerdose of osmotic colonic evacuant than previous colonic cleansingsystems.

The phrase “osmotic colonic evacuant,” as used herein, refers to anycomposition that induces water infusion and retention into theintestinal lumen when the composition is administered to a subject.Compositions of an osmotic colonic evacuant include solids, powders,gels, or liquids. A liquid composition of an osmotic colonic evacuantmay be constituted from a solid, powder, or gel composition using aphysiologically acceptable carrier (e.g., water). A liquid compositionof an osmotic colonic evacuant suitable for administration also may beconstituted from liquid concentrate form using a physiologicallyacceptable carrier (e.g., water) as diluent.

The term “cathartic,” as used herein, refers to any composition thatacts as a colonic evacuant for cleaning the bowels effective forcolonoscopy.

The chemical composition of an osmotic colonic evacuant may be aphosphate-based cathartic, for example, sodium dihydrogen phosphate,disodium hydrogen phosphate, sodium biphosphate, sodium acidpyrophosphate, or mixtures thereof; or a sulfate-based cathartic, forexample, sodium picosulfate and sodium sulfate, or mixtures thereof; ormagnesium-based cathartic, for example, magnesium citrate, magnesiumhydroxide, magnesium sulfate, magnesium oxide, or mixtures thereof; ormagnesium sulfate (Epsom salts). Preferred osmotic colonic evacuantsinclude magnesium sulfate or a mixture of sodium dihydrogen phosphateand disodium hydrogen phosphate. In one embodiment, the preferredosmotic colonic evacuant is the commercially available phosphate saltcathartic FLEET® PHOSPHO-SODA® (C.B. Fleet, Lynchburg, Va.; NationalFormulary Monograph USP 23/NF18, p. 1430), which includes sodiumdihydrogen phosphate, monohydrate (NaH₂PO₄.H₂O) (monobasic sodiumphosphate) and disodium hydrogen phosphate, heptahydrate (Na₂HPO₄.H₂O)(dibasic sodium phosphate) in water. A 45 mL dose contains 21.6 gmonobasic sodium phosphate, and 8.1 g dibasic sodium phosphate.

As the first dose of the two dose treatment, preferably 15 to 25 gmonobasic sodium phosphate is orally administered, for example 20 to 23g monobasic sodium phosphate, including 21.6 g. The first dose alsopreferably contains 5.5 to 9.4 g dibasic sodium phosphate, for example7.5 to 8.6 g dibasic sodium phosphate, including 8.1 g dibasic sodiumphosphate.

As the second dose of the two dose treatment, preferably 55 to 95% ofthe first dose is orally administered, and is always less than the firstdose. For example, 60 to 90% of the first dose may be used, including 60to 70 or 80% of the first dose, such as 66%. For example, if the firstdose is (i) 15 g, (ii) 20 g, (iii) 21.6 g, (iv) 23 g or (v) 25 gmonobasic sodium phosphate, then the second dose could correspond to thefollowing amounts of monobasic sodium phosphate: (i) 8.25 g to 14.25 g,including 9.0 g, 9.9 g, 10.5 g, 12.0 g and 13.5 g; (ii) 11.0 g to 19.0g, including 12.0 g, 13.2 g, 14.0 g, 16.0 g and 18.0 g; (iii) 11.88 g to20.52 g, including 12.96 g, 14.26 g, 15.12 g, 17.28 g and 19.44 g; (iv)12.65 g to 21.85 g, including 13.8 g, 15.18 g, 16.1 g, 18.4 g and 20.7g; or (v) 13.75 g to 23.75 g, including 15.0 g, 16.5 g, 17.5 g, 20.0 g,and 22.5 g. Also as an example, if the first dose contains (i) 5.5 g,(ii) 7.5 g, (iii) 8.1 g, (iv) 8.6 g or (v) 9.4 g dibasic sodiumphosphate, then the second dose could correspond to the followingamounts of dibasic sodium phosphate: (i) 3.02 g to 5.22 g, including 3.3g, 3.63 g, 3.85 g, 4.4 g and 4.95 g; (ii) 4.12 g to 7.12 g, including4.5 g, 4.95 g, 5.25 g, 6.00 g and 6.75 g; (iii) 4.45 g to 7.70 g,including 4.86 g, 5.35 g, 5.67 g, 6.48 g and 7.29 g; (iv) 4.73 g to 8.17g, including 5.16 g, 5.68 g, 6.02 g, 6.88 g and 7.74 g; or (v) 5.17 g to8.93 g, including 5.64 g, 6.20 g, 6.58 g, 7.52 g and 8.46 g.

Preferred phosphate salt cathartics include from 0.05 to 1.5 gram/mL ofmonobasic sodium phosphate and from 0.02 to 0.6 gram/mL of dibasicsodium phosphate. More preferably, the osmotic colonic evacuants of thephosphate salt cathartic variety may also include from 0.25 to 1 or from0.4 to 1 gram/mL of monobasic sodium phosphate and from 0.1 to 0.4 orfrom 0.13 to 0.25 gram/mL of dibasic sodium phosphate. At present, anespecially preferred phosphate salt cathartic includes about 0.48 g/mLof monobasic sodium phosphate and about 0.18 g/mL of dibasic sodiumphosphate. Phosphate salt cathartics that include one phosphate salt,such as dibasic sodium phosphate, also may be used. Preferred phosphatesalt cathartics have a pH from about 4.4 to about 5.2 and may beproduced in multiple ways, such as by combining phosphoric acid withdibasic sodium phosphate or with caustic soda. Osmotic colonic evacuantsof this type are very stable, thus having a long shelf-life, and areconsidered to work in a mild and very effective manner.

The colonic cleansing system may include an osmotic colonic evacuant insolid or powder form that is constituted with a physiologicallyacceptable carrier (e.g., water) immediately prior to administration.Optionally, the physiologically acceptable carrier may be packaged withthe colonic cleansing system. The consumer may provide the source of thephysiologically acceptable carrier apart from the colonic cleansingsystem. An example of a physiologically acceptable carrier includessterile water. The kit will include instructions that direct theconsumer about the types of physiologically acceptable carrier that maybe used to constitute the osmotic colonic evacuant powder in liquidform, as well as the inclusion of any additional materials (e.g.,contents of any flavor packets). Preferably, the osmotic colonicevacuant is not in the form of tablets or capsules.

In another embodiment, the colonic cleansing system may include anosmotic colonic evacuant pre-dissolved in a physiologically acceptablecarrier (e.g., water). The osmotic colonic evacuant may be packaged as atotal dosage form or as individual unit dosage forms (for example, afirst dosage and a separately packaged second dosage). In oneembodiment, the osmotic colonic evacuant is packaged as a total dosageform that is subsequently dispensed as individual unit dosage forms (afirst dosage and a second dosage) using one or more dosage containersthat may be included in the colonic cleansing system. The dosagecontainer may include markings on their surfaces to denote volume filllevels appropriate for consumption of a give volume or amount of theosmotic colonic evacuant. In another preferred embodiment, the osmoticcolonic evacuant is packaged as individual, ready-to-use, unit dosageforms in separate sealed containers.

Prior to consumption, flavorants and/or sweeteners may be added to theosmotic colonic evacuant to increase its palatability. Optionally, theflavorant can be present in the mixture or solution that contains theosmotic colonic evacuant. Alternatively, the flavorant and sweetener canbe individually packaged apart from the osmotic colonic evacuant. Theflavorant may include a citrate-based component. The citrate-basedcomponent may include citric acid, salts, such as sodium or potassiumcitrate, derivatives of citrate, such as a citrate derivatized withester functionality, and the like. The flavorant also may includenatural and/or artificial flavorings, such as natural and/or artificialfruit flavors, to further increase the palatability of the cathartic.Preferred sweeteners include aspartame, sucralose, and acesulfamepotassium, among other ingredients. Preferably, the flavorant andsweetener may be combined as a powered mixture. Examples of suchcombinations include the commercially available aspartame-based drinkmixture, such as the CRYSTAL LIGHT® powder that is available from KraftFoods, Northfield, Ill. (USA) or the N&A Pink Lemonade FL System SugarFAFT523 that is available from WILD Flavors, Inc., Erlanger, Ky. (USA).Both of these powders include aspartame, citric acid, and fruit flavorsthat result in flavored drinks when the powder is combined with water.Examples of compositions and uses of flavorants and sweeteners inphosphate-based cathartics are described, for example, in ASPARTAME ANDCITRATE FLAVORED PHOSPHATE SALT CATHARTIC, U.S. Published PatentApplication publication no. US20060051428 to Ayala et al.

In one preferred embodiment, the flavorants and sweeteners are packagedseparately from the osmotic colonic evacuant in the kit. Optionally, theflavorants and sweeteners can be pre-mixed with the osmotic colonicevacuant composition of the kit.

The colonic cleansing system also includes at least one dosagecontainer. Preferably, at least one surface of the dosage containerincludes markings that denote the volume fill level to achieve a unitdose of the osmotic colonic evacuant when the dosage container is filledwith the osmotic colonic evacuant. The dosage container includesmarkings that denote two different volume fill levels to achievedifferent unit doses of the osmotic colonic evacuant. A first volumefill level will be greater than a second volume fill level to produce afirst unit dose having a given volume of liquid and a second unit dosehaving a lower given volume of liquid. More preferably, a first volumefill level will be greater than a second volume fill level to produce aratio of first unit dose:second unit dose.

In an alternative embodiment, colonic cleansing system may include afirst dosage container and a second dosage container. The two dosagecontainers may be substantially identical or different in form, shape,size, and volume. Preferably, the first dosage container differs fromthe second dosage container in only size and volume such that the seconddosage container may be adapted to fit within the interior of the firstdosage container. Preferably, at least one surface of each dosagecontainer includes markings that denote the volume fill level to achievea unit dose of the osmotic colonic evacuant when the dosage container isfilled with the osmotic colonic evacuant. Preferably, the first dosagecontainer includes at least one marking to denote a volume fill levelcorresponding to a first unit dose of the osmotic colonic evacuant andthe second dosage container includes at least one marking to denote avolume fill level corresponding to a second unit dose of the osmoticcolonic evacuant. Preferably, a first volume fill level will be greaterthan a second volume fill level to produce a first unit dose having agiven volume of liquid and a second unit dose having a lower givenvolume of liquid. More preferably, a first volume fill level will begreater than a second volume fill level to produce a ratio of first unitdose:second unit dose.

Optionally, the dosage container includes an additional marking todenote the volume fill level for a physiologically acceptable carrier(e.g., water). Such a marking is useful to indicate the volume of aphysiologically acceptable carrier to dissolve the contents of packetsof flavorant and/or sweetener. A unit dose of the osmotic colonicevacuant may be added to the dosage container containing the dissolvedflavorant and/or sweetener prior to administering the liquidcomposition. Examples of a dosage container include cups and spoons.

Optionally, the dosage container may contain writings, pictures, symbolsor other information about the use of the dosage container for coloniccleansing or other uses, or other instructions.

The osmotic colonic evacuant may also be present as tablets or capsules.A first dosage unit may be present as one, two, three, four or moretablets or capsules, and the second dosage unit may be present as one,two, three, four or more tablets or capsules. The tablets or capsulesmay all be the same size or may be different sizes. The first dosageform and the second dosage form may be pre-measured and separatelypackaged, for example the tablets or capsules may be present in a firstpackage for the first dose, and a separate package for the second dose.

Finally, the colonic cleansing system will include instructionsdirecting the subject on the use of the contents of the system. For onepreferred embodiment, the instructions will direct the subject toconstitute an osmotic colonic evacuant powder, flavorant powder andsweetener powder into an appropriate volume of a physiologicallyacceptable carrier (e.g., water). The appropriate volume is at leastsufficient to provide for a first unit dose and a second unit dose of aliquid osmotic colonic evacuant. The instructions may direct the subjectto fill at least one dosage container with the constituted liquidosmotic colonic evacuant to a first volume fill level corresponding to afirst unit dose and to consume the contents of the dosage container. Theinstructions may direct the subject to allow for a period of time tolapse, after which the subject is directed to fill the at least onedosage container with the constituted liquid osmotic colonic evacuant toa second volume fill level corresponding to a second unit dose andconsume the contents of the dosage container. Preferably, theinstructions would direct the subject to consume a first unit dose and asecond unit dose of the constituted osmotic colonic evacuant where theratio of first unit dose:second unit dose is greater than 1.00. Mostpreferably, the instructions would direct the subject to consume a 45 mLfirst unit dose and a 30 mL second unit dose of the constituted osmoticcolonic evacuant comprising FLEET® PHOSPHO-SODA® (C.B. Fleet, Lynchburg,Va.; National Formulary Monograph USP 23/NF18, p. 1430), optionallysupplemented with a flavorant and a sweetener.

The markings on the dosage container(s) are particularly advantageousfor kits that contain a total dosage form because such markingsfacilitate the accurate dispensing of the appropriate volume of theosmotic colonic evacuant for consumption. In the case of kits containingindividual dosage unit forms, the volume of each dosage form will bepre-determined by the fill capacity of each sealed container. Thus, theinstructions of such kits need only direct the consumer to pour thecontents of a given individual dosage unit form into the dosagecontainer for consumption without reference to markings on the dosagecontainer.

FIG. 1 depicts a colonic cleansing kit 100 having aspects of the presentinvention. The kit 100 includes an exterior package 102, one or moredosage containers 106, one or more sealed containers 110 having a sealedtop 112, one or more envelope containers 118 and 120 and an instructionpamphlet 122. The exterior package 102 may be composed of paper and/orplastic components and may be imprinted with descriptive productinformation 104. The exterior package 102 may enclose multiplecontainers, such as containers 106, 114, 116, 118, and 120, one or moresupporting structures for the multiple containers, usually having paperand/or plastic components, and a pamphlet 122 containing instructionsfor use 124, and the like. The instruction pamphlet 122 includesdirections regarding how to prepare the osmotic colonic evacuantcomposition (e.g., FLEET® PHOSPHO-SODA® liquid with the flavorant andsweetener) and when to consume the colonic cleansing composition inrelation to the time of a colonoscopy procedure. The supportingstructures may be formed from stiff paper, STYROFOAM', and the like.

The surface of one or more dosage containers 106 may have optionalmarkings 108 to denote volume fill levels. The containers 110 may befitted with screw-lid tops 112 to provide an air-tight seal. The sizesof containers 110 are adapted to contain a first volume 114 and a secondvolume 116 of an osmotic colonic evacuant. Containers 110 include theosmotic colonic evacuant. The containers 118 and 120 may include theflavorant, sweetener and the like. The surface of one or more dosagecontainers 106 may include writings, pictures, symbols or otherinformation about the use of the dosage container for colonic cleansingor other uses. The containers may take the form of bottles, tubs,sachets, envelopes, tubes, ampoules, and the like, which may be formedin part or in whole from plastic, glass, paper, foil, MYLAR®, wax, andthe like. The containers may be equipped with fully or partiallydetachable lids that may initially be part of the containers or may beaffixed to the containers by mechanical, adhesive, or other means.

By orally administering the compositions of the present invention to asubject, the colon may be cleansed. A first aliquot of the compositionmay be administered to the subject about 14 hours prior to thecolonoscopy. This initial dose is followed by a second aliquot of thecomposition administered about 3 hours prior to the colonoscopy. Asurprising and unexpected finding of the present invention is thateffective colonic cleansing suitable for colonoscopy examination can beaccomplished with consumption of a lower second dose of the osmoticcolonic evacuant relative to the first dose of the osmotic colonicevacuant consumed. The subject should consume large amounts of liquids,3 to 4 Liters for example, in addition to the composition to maintainadequate hydration. These additional liquids may include aqueoussolutions that include oral re-hydration salts and/or electrolytes, suchas HYDRALIFE™ and other oral re-hydration beverages.

While various embodiments of the invention have been described, it willbe apparent to those of ordinary skill in the art that other embodimentsand implementations are possible within the scope of the invention.Accordingly, the invention is not to be restricted except in light ofthe attached claims and their equivalents.

1. A method of colonic cleansing, comprising: administering orally afirst dose of a liquid osmotic colonic evacuant composition; andadministering orally a second dose of the liquid osmotic colonicevacuant composition, wherein the second dose comprises an amount of theliquid osmotic colonic evacuant composition that is 55% to 95% of theamount of the first dose of the liquid osmotic colonic evacuantcomposition.
 2. A method of claim 1, wherein the liquid osmotic colonicevacuant composition comprises a phosphate cathartic.
 3. The method ofclaim 2, wherein the phosphate cathartic comprises monobasic sodiumphosphate and dibasic sodium phosphate.
 4. The method of claim 1,wherein the second dose comprises an amount that is 60% to 80% of theamount of the first dose.
 5. The method of claim 3, wherein the firstdose of the phosphate cathartic comprises from 15 to 25 g monobasicsodium phosphate and from 5.5 to 9.4 g dibasic sodium phosphate.
 6. Themethod of claim 3, wherein the first dose of the phosphate catharticcomprises 20 to 23 g monobasic sodium phosphate and 7.5 to 8.6 g dibasicsodium phosphate. 7-9. (canceled)
 10. The method of claim 3, furthercomprising mixing the phosphate cathartic with a flavorant and asweetener.
 11. The method of claim 3, wherein the phosphate catharticcomprises a concentrate.
 12. (canceled)
 13. The method of claim 3,further comprising waiting at least three hours between administeringthe first dose and the second dose.
 14. A kit for colonic cleansing,comprising: a first dose of an osmotic colonic evacuant composition, anda second dose of the osmotic colonic evacuant composition, wherein thesecond dose comprises an amount of the osmotic colonic evacuantcomposition that is 55% to 95% of the amount of the first dose of theosmotic colonic evacuant composition, and the osmotic colonic evacuantis not in the form of tablets or capsules.
 15. A kit of claim 14,wherein the osmotic colonic evacuant composition comprises a phosphatecathartic.
 16. The kit of claim 15, wherein the phosphate catharticcomprises monobasic sodium phosphate and dibasic sodium phosphate. 17.The kit of claim 14, wherein the second dose comprises an amount that is60% to 80% of the amount of the first dose.
 18. The kit of claim 16,wherein the first dose of the phosphate cathartic comprises from 15 to25 g monobasic sodium phosphate and from 5.5 to 9.4 g dibasic sodiumphosphate.
 19. The kit of claim 16, wherein the first dose of thephosphate cathartic comprises 20 to 23 g monobasic sodium phosphate and7.5 to 8.6 g dibasic sodium phosphate. 20-22. (canceled)
 23. The kit ofclaim 16, wherein the first dose and the second dose of the phosphatecathartic are in a single sealed container.
 24. The kit of claim 16,wherein the first dose and the second dose of the phosphate catharticare in separate sealed containers.
 25. The kit of claim 16, furthercomprising a flavorant and a sweetener.
 26. (canceled)
 27. The kit ofclaim 16, wherein the phosphate cathartic comprises powder. 28-31.(canceled)
 32. The kit of claim 16, further comprising a dosagecontainer.
 33. (canceled)
 34. A kit for colonic cleansing, comprising:an osmotic colonic evacuant composition; and at least one dosagecontainer, wherein the at least one dosage container has markings todenote a first dose and a second dose, and the second dose comprises anamount that is 55% to 95% of the amount of the first dose.
 35. The kitof claim 34, wherein osmotic colonic evacuant composition comprises aphosphate cathartic.
 36. The kit of claim 34, wherein the phosphatecathartic comprises monobasic sodium phosphate and dibasic sodiumphosphate.
 37. The kit of claim 34, wherein the second dose comprises anamount that is 60% to 80% of the amount of the first dose.
 38. The kitof claim 36, further comprising a flavorant and a sweetener. 39-42.(canceled)